U.S. patent number 5,962,705 [Application Number 09/192,502] was granted by the patent office on 1999-10-05 for process for preparing derivatives of the taxoid family.
This patent grant is currently assigned to Rhone-Poulenc Rorer S.A.. Invention is credited to Eric Didier, Patrick Leon, Gilles Oddon, Denis Pauze, Didier Riguet.
United States Patent |
5,962,705 |
Didier , et al. |
October 5, 1999 |
Process for preparing derivatives of the taxoid family
Abstract
The present invention relates to a novel process for preparing
dialkoxy derivatives of the taxoid family by direct alkylation of
the two positions 7 and 10 of deacetylbaccatin or derivatives
thereof which are esterified in position 13.
Inventors: |
Didier; Eric (Paris,
FR), Oddon; Gilles (Lyon, FR), Pauze;
Denis (Solaize, FR), Leon; Patrick (Tassin La
Demi Lune, FR), Riguet; Didier (Serezin Du Rhone,
FR) |
Assignee: |
Rhone-Poulenc Rorer S.A.
(Antony Cedex, FR)
|
Family
ID: |
9513490 |
Appl.
No.: |
09/192,502 |
Filed: |
November 17, 1998 |
Foreign Application Priority Data
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Nov 18, 1997 [FR] |
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97 14442 |
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Current U.S.
Class: |
549/510; 548/215;
549/511 |
Current CPC
Class: |
A61P
35/00 (20180101); A61P 31/00 (20180101); C07D
305/14 (20130101); Y02P 20/55 (20151101) |
Current International
Class: |
C07D
305/00 (20060101); C07D 305/14 (20060101); C07D
305/14 (); C07D 263/06 () |
Field of
Search: |
;549/510,511 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0400971B1 |
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Dec 1990 |
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EP |
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0617018A1 |
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Sep 1994 |
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EP |
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0728724A1 |
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Aug 1996 |
|
EP |
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WO 94/07878 |
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Apr 1994 |
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WO |
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WO 95/25728 |
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Sep 1995 |
|
WO |
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WO 95/29926 |
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Nov 1995 |
|
WO |
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WO 96/30355 |
|
Oct 1996 |
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WO |
|
Primary Examiner: Trinh; Ba K.
Attorney, Agent or Firm: Finnegan, Henderson, Farabow,
Garrett & Dunner, L.L.P.
Claims
We claim:
1. A process, comprising the step of alkylating the hydroxyl
functions at the 7-position and 10-position of a compound of
formula (V): ##STR9## wherein A represents hydrogen, a side chain
of formula (Ic), or an oxazolidine of formula (Id): ##STR10##
wherein: G represents a hydroxyl protecting group;
R.sub.1 represents:
a straight or branched alkyl radical containing 1 to 8 carbon
atoms, a straight or branched alkenyl radical containing 2 to 8
carbon atoms, a straight or branched alkynyl radical containing 2
to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon
atoms, a phenyl or .alpha.- or .beta.-naphthyl radical,
unsubstituted or substituted with one or more atoms or radicals
chosen from halogen atoms and alkyl, alkenyl, alkyny, aryl,
arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl,
hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino,
alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl,
alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano,
nitro and trifluoromethyl radicals, or
a 5-membered aromatic heterocycle containing one or more hetero
atoms, which may be identical or different, chosen from nitrogen,
oxygen or sulphur atoms, said 5-membered aromatic heterocycle being
unsubstituted or substituted with one or more of halogen atoms or
alkyl, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino,
acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl,
dialkylcarbamoyl, or alkoxycarbonyl radicals,
wherein when R.sub.1 is a substituted phenyl radical, a substituted
.alpha.- or .beta.-naphthyl radical, or a substituted aromatic
heterocycle, the alkyl radical substituent or the alkyl portion of
another radical substituent contains 1 to 4 carbon atoms, the
alkenyl or alkynyl radical substituent contains 2 to 8 carbon
atoms, and the aryl radical substituent is a phenyl or .alpha.- or
.beta.-naphthyl radical;
R.sub.2 represents:
1) a benzoyl radical, unsubstituted or substituted with one or more
atoms or radicals, which may be identical or different, chosen from
halogen atoms and alkyl radicals containing 1 to 4 carbon atoms,
alkoxy radicals containing 1 to 4 carbon atoms or trifluoromethyl,
thenoyl or furoyl radicals, or
2) a radical R'.sub.2 --C--CO--, wherein R'.sub.2 represents:
an alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical
containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to
8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon
atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or a
bicycloalkyl radical containing 7 to 10 carbon atoms, these
radicals being unsubstituted or substituted with one or more
substituents chosen from halogen atoms and hydroxyl radicals,
alkoxy radicals containing 1 to 4 carbon atoms, dialkylamino
radicals in which each alkyl part contains 1 to 4 carbon atoms,
piperidino or morpholino radicals, 1-piperazinyl radicals
(unsubstituted or substituted in position 4 with an alkyl radical
containing 1 to 4 carbon atoms or with a phenyl alkyl radical in
which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl
radicals containing 3 to 6 carbon atoms, cycloalkenyl radicals
containing 4 to 6 carbon atoms, phenyl radicals (unsubstituted or
substituted with one or more atoms or radicals chosen from halogen
atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy
radicals containing 1 to 4 carbon atoms), cyano or carboxyl
radicals or alkoxycarbonyl radicals in which the alkyl part
contains 1 to 4 carbon atoms,
a phenyl or .alpha.- or .beta.-naphthyl radical, unsubstituted or
substituted with one or more atoms or radicals chosen from halogen
atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy
radicals containing 1 to 4 carbon atoms or a 5-membered aromatic
heterocyclic radical preferably chosen from furyl and thienyl
radicals,
or a saturated heterocyclic radical containing 4 to 6 carbon atoms,
unsubstituted or substituted with one or more alkyl radicals
containing 1 to 4 carbon atoms; and
R.sub.3 and R.sub.4, which may be identical or different,
represent:
hydrogen or alkyl, aryl, halo, alkoxy, arylalkyl, alkoxyaryl,
haloalkyl or haloaryl radicals, or R.sub.3 and R.sub.4 together
form a 4- to 7-membered ring;
wherein the alkylation is carried out in the presence of:
(i) an alkylating agent, wherein the alkylating agent is an alkyl
halide, an alkyl sulphate, or an oxonium; and
(ii) an anionization agent.
2. A process according to claim 1, wherein the compound of formula
(V) is 10-deacetylbaccatin.
3. A process according to claim 1, wherein the alkylating agent is
a boric salt of a trialkyloxonium.
4. A process according to claim 1, wherein the alkylating agent is
trimethyloxonium tetrafluoroborate.
5. A process according to claim 1, wherein the alkylating agent is
an alkyl iodide.
6. A process according to claim 1, wherein the alkylating agent is
methyl iodide.
7. A process according to claim 1, wherein the alkylating agent is
methyl sulphate.
8. A process according to claim 1, wherein the anionization agent
is a strong base in anhydrous medium.
9. A process according to claim 8, wherein the strong base is an
alkali metal hydride, an alkali metal alkoxide, silver oxide,
1,8-bis(dimethylamino)naphthalene, an alkali metal amide mixed with
an alkali metal t-butoxide, or an alkyllithium mixed with an alkali
metal t-butoxide.
10. A process according to claim 8, wherein the strong base is
sodium or potassium hydride.
11. A process according to claim 8, wherein the strong base is
potassium hydride.
12. A process according to claim 8, wherein the strong base is
potassium tert-butoxide.
13. A process according to claim 1, wherein the alkylating agent is
methyl iodide and the anionization agent is potassium hydride.
14. A process according to claim 1, wherein the reaction is carried
out in an organic medium under reaction conditions wherein the
organic medium is inert.
15. A process according to claim 14, wherein the organic medium is
an ether.
16. A process according to claim 14, wherein the organic medium is
tetrahydrofuran or dimethoxyethane.
17. A process according to claim 1, wherein the alkylation is
carried out in the presence of silver oxide and an aromatic or
polar aprotic solvent.
18. A process according to claim 1, wherein the alkylation is
carried out in the presence of a mixture of
1,8-bis(dimethylamino)-naphthalene, trimethyloxonium
tetrafluoroborate, and ethyl acetate.
19. A process according to claim 1, wherein the anionization agent
and the substrate are present in a molar ratio of at least about
2.
20. A process according to claim 1, wherein the anionization agent
and the substrate are present in a molar ratio of from about 2 to
about 20.
21. A process according to claim 1, wherein the alkylating agent
and the substrate are present in a molar ratio of at least about
2.
22. A process according to claim 1, wherein the alkylating agent
and the substrate are present in a molar ratio of from about 2 to
about 40.
23. A process according to claim 1, wherein the alkylation is
carried out at a reaction temperature of from -30.degree. C. to
80.degree. C.
24. A process according to claim 1, wherein the alkylation step
involves simultaneous alkylation of the hydroxyl functions at the
7-position and 10-position of the compound of formula (V).
Description
The present invention relates to a novel process for preparing
dialkoxy derivatives of the taxoid family. The expression dialkoxy
derivatives of the taxoid family is understood to refer to
derivatives bearing an alkoxy unit in positions 7 and 10 of the
baccatin ring-system and optionally bearing a
.beta.-phenylisoserine chain in position 13.
More specifically, the expression dialkoxy derivatives of the
taxoid family is understood to refer to the derivatives
corresponding to the following general formula: ##STR1## in which:
the groups R represent the same straight or branched alkyl group
containing 1 to 6 carbon atoms
Z represents hydrogen or a unit of formula ##STR2## in which
R.sub.1 represents 1) a straight or branched alkyl radical
containing 1 to 8 carbon atoms, a straight or branched alkenyl
radical containing 2 to 8 carbon atoms, a straight or branched
alkynyl radical containing 2 to 8 carbon atoms, a cycloalkyl
radical containing 3 to 6 carbon atoms, a phenyl or .alpha.- or
.beta.-naphthyl radical optionally substituted with one or more
atoms or radicals chosen from halogen atoms and alkyl, alkenyl,
alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio,
hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino,
aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino,
carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl,
dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, or
2) a 5-membered aromatic heterocycle containing one or more hetero
atoms, which may be identical or different, chosen from nitrogen,
oxygen and sulphur atoms, and optionally substituted with one or
more substituents, which may be identical or different, chosen from
halogen atoms and alkyl, aryl, amino, alkylamino, dialkylamino,
alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl,
carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, and alkoxycarbonyl
radicals,
3) it being understood that, in the substituents on the phenyl,
.alpha.- or .beta.-naphthyl radicals and the aromatic heterocycles,
the alkyl radicals and the alkyl portions of the other radicals
contain 1 to 4 carbon atoms and that the alkenyl and alkynyl
radicals contain 2 to 8 carbon atoms and that the aryl radicals are
phenyl or .alpha.- or .beta.-naphthyl radicals,
R.sub.2 represents
1) a benzoyl radical optionally substituted with one or more atoms
or radicals, which may be identical or different, chosen from
halogen atoms and alkyl radicals containing 1 to 4 carbon atoms,
alkoxy radicals containing 1 to 4 carbon atoms or trifluoromethyl,
thenoyl or furoyl radicals, or
2) a radical R'.sub.2 -O-CO- in which R'.sub.2 represents: an alkyl
radical containing 1 to 8 carbon atoms, an alkenyl radical
containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to
8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon
atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or a
bicycloalkyl radical containing 7 to 10 carbon atoms, these
radicals optionally being substituted with one or more substituents
chosen from halogen atoms and hydroxyl radicals, alkoxy radicals
containing 1 to 4 carbon atoms, dialkylamino radicals in which each
alkyl part contains 1 to 4 carbon atoms, piperidino or morpholino
radicals, 1-piperazinyl radicals (optionally substituted in
position 4 with an alkyl radical containing 1 to 4 carbon atoms or
with a phenyl alkyl radical in which the alkyl part contains 1 to 4
carbon atoms), cycloalkyl radicals containing 3 to 6 carbon atoms,
cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl
radicals (optionally substituted with one or more atoms or radicals
chosen from halogen atoms and alkyl radicals containing 1 to 4
carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms),
cyano or carboxyl radicals or alkoxycarbonyl radicals in which the
alkyl part contains 1 to 4 carbon atoms, a phenyl or .alpha.- or
.beta.-naphthyl radical optionally substituted with one or more
atoms or radicals chosen from halogen atoms and alkyl radicals
containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4
carbon atoms or a 5-membered aromatic heterocyclic radical
preferably chosen from furyl and thienyl radicals, or a saturated
heterocyclic radical containing 4 to 6 carbon atoms, optionally
substituted with one or more alkyl radicals containing 1 to 4
carbon atoms.
Among the products of formula (Ia) which are the subject of the
process of the present invention, the preferred ones are those for
which:
Z represents hydrogen or a radical of formula (Ib) in which
R.sub.1 represents a phenyl radical
R.sub.2 represents a tert-butoxycarbonyl radical or a benzoyl
radical.
The products most particularly preferred are those for which:
R.sub.1 represents a phenyl radical
R.sub.2 represents a tert-butoxycarbonyl radical
R represents a methyl radical.
It is known practice, according to patent WO 96/30355, to prepare a
derivative according to the present invention by two processes.
According to a first, multi-step process, starting with
10-deacetylbaccatin III of formula: ##STR3## it is selectively
protected in positions 7 and 13, for example in the form of a
disilyl ether, followed by the action of a product of general
formula :
in which R represents a radical as defined above and X represents a
reactive ester residue such as a sulphuric or sulphonic ester
residue, or a halogen atom, to give a product bearing the unit --OR
in position 10 and silyl groups in positions 7 and 13. Next, the
silyl protecting groups are replaced with hydrogen atoms to give a
compound still bearing the group --OR in position and OH groups in
positions 7 and 13. This derivative is selectively etherified in
position 7 by reaction with the derivative of formula (III) to give
the derivative of formula (I) in which Z is equal to hydrogen.
The final step consists in esterifying in position 13, according to
a process which is known per se, the derivatives of formula (Ia),
in which Z represents hydrogen, in the presence of a .beta.-lactam,
for example according to the process described in patent EP
617,018, or in the presence of an oxazolidine, for example
according to the process described in patent Wo 96/30355 mentioned
above.
According to a second process described in the same patent WO
96/30355, the products of general formula (Ia) can be obtained
according to a 5-step process starting from the product of general
formula (II). In a first step, protection of positions 7 and 10 is
carried out, followed by esterification at position 13 in the
presence of a .beta.-lactam, for example according to the process
described in patent EP 617,018, or in the presence of an
oxazolidine, for example as described in patent WO 96/30355
mentioned above. After deprotection of the protecting groups in
positions 7 and 10, an ester of formula (Ia) is thus obtained in
which Z is other than hydrogen and R represents hydrogen. The
following step consists in reacting positions 7 and 10
simultaneously by the action of a reagent formed in situ from a
sulphoxide of formula (IV) and acetic anhydride (Pummerer-type
reaction),
in which R has the same meaning as above, in order to form an
alkylthioalkyloxy type intermediate on positions 7 and 10.
The final step which gives the desired compound of formula (Ia) is
carried out on the intermediate compound obtained above by the
action of activated Raney nickel.
Generally, the action of the reagent formed in situ from the
sulphoxide of general formula (IV), preferably dimethyl sulphoxide
and acetic anhydride, is carried out in the presence of acetic acid
or an acetic acid derivative such as a haloacetic acid, at a
temperature of between 0 and 50.degree. C.
Generally, the action of activated Raney nickel in the presence of
an aliphatic alcohol or an ether is carried out at a temperature of
between -10 and 60.degree. C.
The set of processes described in this prior art has never made it
possible to reach directly, in one step, the dialkoxy derivatives
in positions 7 and 10 of 10-deacetylbaccatin III.
The present invention makes it possible to achieve this aim. It
allows the selective and simultaneous, direct one-step alkylation
of the two hydroxyl functions in positions 7 and 10 of
10-deacetylbaccatin or derivatives thereof which are esterified in
position 13, of formula (V) ##STR4## in which A represents hydrogen
or aside chain of formula (Ic) below: ##STR5## in which G
represents a protecting group for the hydroxyl function or an
oxazolidine unit of formula (Id): ##STR6## in which R.sub.1 and
R.sub.2 have the same meanings as above and R.sub.3 and R.sub.4 are
chosen from hydrogen or from alkyl, aryl, halo, alkoxy, arylalkyl,
alkoxyaryl, haloalkyl and haloaryl radicals, it being possible for
the substituents optionally to form a 4- to 7-membered ring.
It is preferred to use lo-deacetylbaccatin as starting material,
i.e. the product of formula (II), which makes the process
considerably cost-effective and moreover avoids the intermediate
protection and deprotection steps required in the processes of the
prior art.
Among the groups G for protecting the hydroxyl function in formula
(Ic), it is generally preferred to select the set of protecting
groups described in books such as Greene and Wuts Protective Groups
in Organics Synthesis 1991, John Wiley & Sons, and MacOmie,
Protective Groups in Organic Chemistry, 1975, Plenum Press, and
which are deprotected under conditions which degrade the rest of
the molecule little or not at all, such as, for example:
ethers and preferably ethers such as methoxymethyl ether,
1-ethoxyethyl ether, benzloxymethyl ether, p-methoxybenzyloxymethyl
ether, benzyl ethers optionally substituted with one or more groups
such as methoxy, chloro or nitro, 1-methyl-1-methoxyethyl ether,
2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether or
silyl ethers such as trialkylsilyl ethers,
carbonates such as trichloroethyl carbonates.
More particularly, the radicals R.sub.3 and R.sub.4 of the general
formula (Id) are chosen from those described in patent WO 94/07878,
and the derivatives in which R.sub.3 is hydrogen and R.sub.4 is a
p-methoxyphenyl radical are more particularly preferred.
The alkylating agent is chosen from:
alkyl halides and preferably, among those, alkyl iodides (RI)
alkyl sulphates such as methyl-sulphate
oxoniums such as boric salts of trialkyloxoniums, in particular
trimethyloxonium tetrafluoroborate (Me.sub.3 OBF.sub.4).
Methyl iodide is preferably used.
The alkylating agent is used in the presence of an anionization
agent such as one or more strong bases in anhydrous medium.
Among the bases which can be used in anhydrous medium, mention may
be made of:
alkali metal hydrides such as sodium or potassium hydride
alkali metal alkoxides such as potassium tert-butoxide
silver oxide Ag.sub.2 O
1,8-bis(dimethylamino)naphthalene
mixtures of mono- or bimetallic base such as those described, for
example, in publications such as P. Caubere Chem. Rev. 1993, 93,
2317-2334 or M. Schlosser Mod. Synth. Methods (1992), 6, 227-271;
in particular, the alkyllithium/alkali metal t-butoxide or alkali
metal amides/alkali metal t-butoxide combinations are preferred.
One of the two bases can be generated "in situ".
Among all of the possible combinations of alkylating agent and
anionization agent, it is preferred to use methyl iodide in the
presence of potassium hydride.
Preferably, the reaction is carried out in an organic medium which
is inert under the reaction conditions. Among the solvents, it is
preferred to use:
ethers such as tetrahydrofuran or dimethoxyethane
when silver oxide is used, it is preferred to use polar aprotic
solvents such as dimethylformamide or aromatic solvents such as
toluene
when 1,8-bis(dimethylamino)naphthalene is used, it is preferred to
use esters, for example alkyl esters such as ethyl acetate.
For better implementation of the invention, it is preferred to use
a molar ratio between the anionization agent and the substrate of
greater than 2 and preferably between 2 and 20.
It is also preferred to use a molar ratio between the alkylating
agent and the substrate of greater than 2 and preferably between 2
and 40.
It is preferred to use a reaction temperature of between
-30.degree. C. and 80.degree. C.
The reaction time advantageously ranges between a few hours and 48
hours depending on the reagents chosen.
After the alkylation step, when the latter is carried out on
10-deacetylbaccatin, the esterification step is then performed in a
known manner, for example according to the processes described in
patents EP 617,018 or WO 96/30355 mentioned above.
Thus, according to a first three-step process, 10-deacetylbaccatin
is used to begin with, first carrying out the dialkylation using an
alkylating agent in the presence of a strong base, and in a second
step the 10-deacetylbaccatin dietherified in positions 7 and 10 is
coupled in position 13 with a suitably protected .beta.-lactam in
the presence of an activating agent chosen from tertiary amines and
metallic bases, to form an alkoxide in position 13. The side chain
is then deprotected by the action of an inorganic or organic
acid.
Thus, according to a second three-step process, 10-deacetylbaccatin
is used to begin with, first carrying out the dialkylation using an
alkylating agent in the presence of a strong base, and in a second
step the 10-deacetylbaccatin dietherified in positions 7 and 10 is
coupled in position 13 with an oxazolidine in the presence of a
coupling agent such as diimides in the presence of an activating
agent such as dialkylaminopyridines. The oxazolidine is opened by
the action of an inorganic or organic acid.
According to a third process, the baccatin suitably protected in
positions 7 and 10 is first esterified in position 13 with a
.beta.-lactam or an oxazolidine in the presence of a coupling agent
and/or an activating agent as described in the above two processes.
After deprotection in positions 7 and 10, the dietherification in
positions 7 and 10 is carried out with an alkylating agent in the
presence of a strong base. The side chain is then deprotected by
the action of an inorganic or organic acid.
The present invention will be described more fully with the aid of
the examples which follow, which should not be considered as
limiting the invention.
EXAMPLES
All of these tests are carried out under argon and using anhydrous
solvents.
Example 1
Silver oxide/methyl iodide/toluene/10-DAB
Silver oxide (255 mg, 1.1 mmol, 2.2 equiv.) is added to a
suspension of 10-deacetylbaccatin III (272 mg, 0.5 mmol) in a
toluene/methyl iodide mixture (3/2; 2.5 ml) at 0.degree. C. The
mixture is allowed to return gradually to room temperature. After
reaction for 5 h, the reaction mixture is heated to 60.degree. C.
After stirring for 24 h at 60.degree. C, an excess of reagents is
added: silver oxide (2.times.255 mg) and methyl iodide (2.times.1
ml). After heating for a further 36 hours, the reaction mixture is
filtered through a sinter funnel and the filtrate is evaporated.
According to the HPLC analysis, the reaction medium contains 11.5%
(by internal standardization of the areas) of
7,10-dimethoxy-10-deacetylbaccatin.
Example 2
Silver oxide/methyl iodide/pyridine/toluene/10-DAB
Pyridine (8 .mu.l, 0.1 mmol, 0.2 equiv.) and then silver oxide (255
mg, 1.1 mmol, 2.2 equiv.) are successively added to a suspension of
10-deacetylbaccatin III (272 mg, 0.5 mmol) in a toluene/methyl
iodide mixture (3/2; 2.5 ml) at room temperature. The reaction
mixture is then heated to 50.degree. C. After stirring for 24 h at
60.degree. C., an excess of reagents is added: silver oxide (255
mg, 1.1 mmol, 2.2 equiv.), pyridine (80 .mu.l, 1 mmol, 2 equiv.)
and methyl iodide (1 ml). After heating for a further 24 h, the
reaction mixture is filtered through a sinter funnel and the
filtrate is diluted with ethyl acetate (40 ml). This phase is
washed with brine (20 ml) separated, dried over sodium sulphate and
evaporated (131 mg). According to the HPLC analysis, the crude
reaction product contains 12.2% (by internal standardization of the
areas) of 7,10-dimethoxy-10-deacetylbaccatin.
Example 3
Silver oxide/methyl iodide/N,N-dimethylformamide/10-DAB
Silver oxide (255 mg, 1.1 mmol, 2.2 equiv.) is added to a solution
of 10-deacetylbaccatin III (272 mg, 0.5 mmol) in an
N,N-dimethylformamide/methyl iodide mixture (3/2; 2.5 ml) at
0.degree. C. The mixture is allowed to return gradually to room
temperature. After stirring for 24 h, the reaction mixture is
diluted with diethyl ether (20 ml) and filtered through a sinter
funnel. The filtrate is washed with water (20 ml). The organic
phase is separated out, dried over sodium sulphate and evaporated
(207 mg). According to the HPLC analysis, the crude reaction
product contains 9.2% (by internal standardization of the areas) of
7,10-dimethoxy-10-deacetylbaccat in.
Example 4
Potassium hydride/methyl iodide/tetrahydrofuran/10-DAB
The potassium hydride as a 20% suspension in a mineral oil (6.0 g,
30 mmol, 3 equiv.) is prewashed with pentane.
A suspension of lo-deacetylbaccatin III (5.23 g, 10 8.5 mmol, 89%
pure) in a tetrahydrofuran/methyl iodide mixture (3/2, 50 ml) is
added dropwise to a suspension of potassium hydride, prewashed with
pentane, in tetrahydrofuran (30 ml) at -30.degree. C. The mixture
is then allowed to return gradually to room temperature. After
stirring for 3 h 30, the reaction mixture is poured into water (150
ml) and diisopropyl ether (250 ml). The mixture is filtered through
a sinter funnel. The precipitate is then collected and washed
separately with water (14 ml). This suspension is again filtered
through a sinter funnel to give, after drying overnight in a
desiccator over P.sub.2 O.sub.5, 3.17 g of
7,10-dimethoxy-10-deacetylbaccatin (HPLC purity: 93% by internal
standardization of the areas). The yield of isolated product is
61%.
Example 5
Potassium t-butoxide/methyl iodide/tetrahydrofuran/10-DAB
A suspension of 10-deacetylbaccatin III (544 mg, 1 mmol) in a
tetrahydrofuran/methyl iodide mixture (3/2, 5 ml) is added dropwise
to a suspension of potassium t-butoxide (336 mg, 3 mmol, 3 equiv.)
in tetrahydrofuran (4 ml) at -30.degree. C. The mixture is then
allowed to return gradually to room temperature. After stirring for
3 h 30, HPLC analysis indicates that the reaction mixture contains
10.0% (by internal standardization of the areas) of
7,10-dimethoxy-10-deacetylbaccatin.
Example 6
Potassium hydride/methyl sulphate/tetrahydrofuran/10-DAB
The potassium hydride as a 20% suspension in a mineral oil (0.6 g,
3 mmol, 3 equiv.) is prewashed with pentane.
A suspension of 10-deacetylbaccatin III (544 mg, 1 mmol) in
tetrahydrofuran (6 ml) and a solution of methyl sulphate (2.0 g, 16
mmol, 16 equiv.) in tetrahydrofuran (2 ml) are simultaneously added
dropwise to a suspension of potassium hydride, prewashed with
pentane, in tetrahydrofuran (3 ml) at -20.degree. C. The mixture is
then allowed to return gradually to room temperature. After
reaction for 8 h, the reaction mixture is poured into water (20 ml)
and placed overnight at 4.degree. C. Diisopropyl ether (20 ml) is
then added and the mixture is filtered through a sinter funnel to
give 220 mg. According to the HPLC analysis, the crude reaction
product contains 98% (by internal standardization of the areas) of
7,10-dimethoxy-10-deacetylbaccatin.
Example 7
Potassium hydride/trimethyloxonium
tetrafluoroborate/tetrahydrofuran/10-DAB
The potassium hydride as a 20% suspension in a mineral oil (0.6 g,
3 mmol, 3 equiv.) is prewashed with pentane.
A suspension of 10-deacetylbaccatin III (544 mg, 1 mmol) in
tetrahydrofuran (3 ml) is added to a suspension of potassium
hydride, prewashed with pentane, and of trimethyloxonium
tetrafluoroborate in tetrahydrofuran (3 mol) at -20.degree. C. The
mixture is then allowed to rise gradually to a temperature of
-10.degree. C. After reaction for two hours, a suspension of
potassium hydride (2 equiv.) in tetrahydrofuran (1 ml) is added.
After reaction for a further two hours, HPLC analysis indicates
that the reaction mixture contains 16.3% (by internal
standardization of the areas) of
7,10-dimethoxy-10-deacetylbaccatin.
Example 8
Potassium hydride/methyl iodide/1,2-dimethoxyethane/10-DAB
The potassium hydride as a 20% suspension in a mineral oil (0.6 g,
3 mmol, 3 equiv.) is prewashed with pentane.
A solution of 10-deacetylbaccatin III (544 mg, 1 mmol) in a
1,2-dimethoxyethane/methyl iodide mixture (3/1, 8 ml) is added
dropwise to a suspension of potassium hydride, prewashed with
pentane, in 1,2-dimethoxyethane (3 ml) at -20.degree. C. The
mixture is then allowed to return gradually to room temperature.
After stirring for 6 h 30, HPLC analysis indicates that the
reaction mixture contains 28.1% (by internal standardization of the
areas) of 7,10-dimethoxy-10-deacetylbaccatin.
Example 9
Potassium hydride/methyl
iodide/tetrahydrofuran/compound (V) with A=(id) (R.sub.1 =phenyl,
R.sub.2 =H, R.sub.3 =t-butoxycarbonyl, R.sub.4
=4-methoxyphenyl)
The potassium hydride as a 20% suspension in a mineral oil (0.145
g, 2.4 equiv.) is prewashed with pentane.
A suspension of
4-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1,7.beta.,10.beta.-trihydro
xy-9-oxotax-11-en-13.alpha.-yl
(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-5-oxazolidin
ecarboxylate (284 mg, 0.3 mmol) in a tetrahydrofuran/methyl iodide
mixture (5/3, 1.6 ml) is added dropwise to a suspension of
potassium hydride, prewashed with pentane, in tetrahydrofuran (0.7
ml) at -78.degree. C. The mixture is then allowed to rise gradually
to a temperature of -15.degree. C. After stirring for 3 h 30, the
reaction mixture is poured into water (15 ml) and ethyl acetate (15
ml). The organic phase is separated out, washed with brine (15 ml),
dried over sodium sulphate, filtered and evaporated (232 mg). HPLC
analysis of the crude product gives an assayed yield of 39% of
4-acetoxy-2.alpha.-benzoyloxy-5.beta.,
20-epoxy-1-hydroxy-9-oxo-7.beta.,10.beta.-dimethoxytax-11-en-13.alpha.-yl
(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-5-oxazolidin
ecarboxylate.
Example 10
Sodium hydride/methyl iodide/tetrahydro-furan/10-DAB
The sodium hydride as a 55% suspension in a mineral oil (0.13 g, 3
mmol, 3 equiv.) is prewashed with pentane.
A suspension of 10-deacetylbaccatin III (544 mg, 1 mmol) in a
tetrahydrofuran/methyl iodide mixture (3/2, 5 ml) is added dropwise
to a suspension of sodium hydride, prewashed with pentane, in
tetrahydrofuran (3 ml) at 0.degree. C. The mixture is then allowed
to return gradually to room temperature. After stirring for 7 h 30,
the reaction mixture is poured into water (25 ml) and diisopropyl
ether (25 ml). A precipitate appears, which is filtered off on a
sinter funnel. 57 mg of product are thus recovered containing 67%
(by internal standardization of the areas) of
7,10-dimethoxy-10-deacetylbaccatin.
Example 11
n-butyllithium/potassium t-butoxide/tetra-hydrofuran/10-DAB
A solution of n-butyllithium in hexane (2 ml, 3 mmol, 3 equiv.) is
evaporated under vacuum. The residue is taken up in tetrahydrofuran
(3 ml), precooled to -78.degree. C. Potassium t-butoxide (336 mg, 3
mmol, 3 equiv.) is then added, followed by addition of a suspension
of 10-deactyl baccatin III (544 mg, 1 mmol) in a
tetrahydrofuran/methyl iodide mixture (5 ml, 3/2). The mixture is
then allowed to return gradually to room temperature. After
reaction for 3 h 45, the mixture is poured into water (10 ml) and
diisopropyl ether (10 ml). After crystallization overnight at
4.degree. C., 75 mg of crystals are recovered containing 61% (by
internal standardization of the areas) of
7,10-dimethoxy-10-deacetylbaccatin.
Example 12
n-butyllithium/potassium
t-butoxide/diisopropylamine/tetrahydrofuran/10-DAB
A solution of n-butyllithium in hexane (2 ml, 3 mmol, 3 equiv.) is
evaporated under vacuum. The residue is taken up with a solution of
diisopropylamine (0.5 ml, 3 mmol, 3 equiv.) in tetrahydrofuran (3
ml), precooled to -78.degree. C. Potassium t-butoxide (336 mg, 3
mmol, 3 equiv.) is then added, followed by addition of a suspension
of 10-deacetylbaccatin III (544 mg, 1 mmol) in a
tetrahydrofuran/methyl iodide mixture (5 ml, 3/2). The mixture is
then allowed to return gradually to room temperature. After
reaction for 19 h, HPLC analysis indicates that the reaction
mixture contains 24% (by internal standardization of the areas) of
7,10-dimethoxy-10-deacetylbaccatin.
Example 13
Sodium amide/t-butanol/tetrahydrofuran/10-DAB
A suspension of sodium amide (173 mg, 4 mmol, 4 equiv.) and of
t-butanol (0.13 ml, 1.3 mmol, 1.3 equiv.) in tetrahydrofuran (2 ml)
is heated at 45.degree. C. for 2 h. After cooling to room
temperature, the mixture is cooled to -50.degree. C. and a
suspension of 10-deacetylbaccatin III (544 mg, 1 mmol) in a
tetrahydrofuran/methyl iodide mixture (3/2, 5 ml) is added
dropwise. The mixture is allowed to rise gradually to -20.degree.
C. After stirring for 2 h 20, the mixture is poured into water (10
ml) and diisopropyl ether (10 ml). The precipitate is filtered off
on a sinter funnel to give 160 mg of crude product containing 37%
(by internal standardization of the areas) of
7,10-dimethoxy-10-deacetylbaccatin.
Example 14
Trimethyloxonium
tetrafluoroborate/1,8-bis(dimethylamino)naphthalene/4 .ANG.
sieves/10-DAB
1,8-bis(dimethylamino)naphthalene (514 mg, 2.4 mmol, 12 equiv.), 4
.ANG. molecular sieves (700 mg) and trimethyloxonium
tetrafluoroborate (296 mg, 2 mmol, 10 equiv.) are successively
added to a suspension of 10-deacetylbaccatin III (109 mg, 0.2 mmol)
in dichloromethane (4 ml) at 25.degree. C. After stirring for 24 h
at room temperature, HPLC analysis indicates that the reaction
mixture contains 7,10-dimethoxy-10-deacetylbaccatin in an assayed
yield of 17%.
Example 15
1,8-bis(dimethylamino)naphthalene (1.2744 g, 5.95 mmol, 12.8
equiv.) and trimethyloxonium tetrafluoroborate (0.7598 g, 14 mmol,
11 equiv.) are successively added to a suspension of
10-deacetylbaccatin III (0.2876 g, 0.46 mmol) in ethyl acetate (7.8
ml) at 20.degree. C. After stirring for 2 hours 20 minutes at a
temperature of between 45-50.degree. C., HPLC analysis indicates
that the reaction mixture contains
7,10-dimethoxy-10-deacetylbaccatin in an assayed yield of 62%.
Analyses for the compound 7,10-dimethoxy-10-deacetylbaccatin
III
The NMR analyses were carried out on a Bruker AM 360 spectrometer
operating at 360 MHz for proton and 90 MHz for carbon-13, and
equipped with a 5 mm proton/carbon-13 dual probe. The chemical
shifts are expressed in ppm; DMSO is used as external reference
(2.44 ppm in the proton spectrum and 39.5 ppm in the carbon
spectrum). The temperature is controlled by a variable-10
temperature unit to 300 K. ##STR7##
______________________________________ .sup.1 H NMR .sup.13 C NMR
Position .delta. (ppm) multiplicity J (Hz) d (ppm)
______________________________________ 1 -- -- -- 75.2 2 5.34
doublet 7.2 74.3 3 3.71 doublet 7.2 47.0 4 -- -- -- 80.0 5 4.93
doublet 9.1 83.2 6 1.44/2.64 multiplet -- 31.7 7 3.76 doubled 10.5/
80.4 doublet 6.5 8 -- -- -- 56.6 9 -- -- -- 205.3 10 4.70 singlet
-- 82.7 11 -- -- -- 132.7 12 -- -- -- 143.9 13 4.61 multiplet --
66.1 14 2.13 multiplet -- 39.3 15(CH.sub.3) 0.90 singlet -- 20.5
26.9 1(OH) 4.33 singlet -- -- 2(PhCOO) 7.5(2H) triplet
165.1(C.dbd.O) 7.6(1H) triplet 130.1/129.4 8.0(ortho doublet 7.5
128.6/133.1 C.dbd.O) 4(Ac) 2.15 singlet -- 169.6 (C.dbd.O)22.3
4(CH.sub.2 O) 3.99 AB system not 76.8 deter- mined 7(OCH.sub.3)
3.17 singlet -- 56.4 8(CH.sub.3) 1.47 singlet -- 10.0 10(OCH.sub.3)
3.25 singlet -- 56.0 12(CH.sub.3) 1.93 singlet -- 15.0 13(OH) 5.25
doublet 4.5 -- ______________________________________
Ms: Direct introduction; ionization mode ESI+ ##STR8## IR
(KBr):
______________________________________ 3552.5 cm.sup.-1 Alcoholic
O--H (secondary) 3434.9 cm.sup.-1 Alcoholic O--H (tertiary)
2972.2-2931.5-2892.6 cm.sup.-1 Hydrocarbon skeleton 2826.9
cm.sup.-1 C--H of the O--CH.sub.3 units 1716-1705.3 cm.sup.-1
C.dbd.O of the OAc and ketone units 1269.7-1250.8 cm.sup.-1
Aromatic ether C--O 1098.3-1068.7 cm.sup.-1 C--O of the alcohols
and cyclic ether ______________________________________
* * * * *